medwireNews: Dose-escalated external-beam radiation therapy (EBRT) prolongs overall survival in men with intermediate- and high-risk, but not low-risk, localised prostate cancer, suggests an analysis of the US National Cancer Database.

“Our results add to the body of evidence questioning aggressive local treatment strategies in men with low-risk prostate cancer but supporting such treatment in men with greater disease severity”, says the team led by Anusha Kalbasi, from the University of Pennsylvania in Philadelphia, USA.

A total of 42,481 men with localised disease who underwent EBRT at an accredited community, academic or comprehensive cancer facility between 2004 and 2006 were categorised by risk and by level of radiation, with 75.6 Gy as the cutoff for the standard (68.4 to <75.6 Gy) and dose-escalation (≥75.6 to 90.0 Gy) groups. The cohorts were followed up for a median of 85 to 86 months.

No significant difference in overall survival was noted between men who received dose-escalated compared with standard-dose EBRT among the 12,229 patients with low-risk prostate cancer as per the National Comprehensive Cancer Network guidelines.

But among the 16,714 intermediate-risk patients and the 13,538 patients with high-risk disease, overall survival was significantly longer in those who received the escalated rather than the standard dose, with inverse probability–weighted propensity score adjusted hazard ratios for death of 0.84 and 0.82, respectively.

And every incremental rise of approximately 2.0 Gy in dose reduced the mortality risk by 7.8% for intermediate-risk patients and by 6.3% for those with high-risk prostate cancer.

Compared with the reference 70.2 Gy subgroup, significant differences in survival were seen for the 81.0 Gy and over 81.0 Gy subgroups in both the intermediate- and high-risk cohorts, and additionally in the 76.0 Gy and 79.2 Gy subgroups for men with intermediate-risk disease.

“These may represent threshold doses that need to be achieved to derive the mortality benefit observed, and beyond this threshold, our data do not exclude the possibility that even higher doses of EBRT, as delivered by approaches such as combined EBRT and brachytherapy, would be associated with better outcomes”, the researchers write in JAMA Oncology.

“However, incremental benefits of dose-escalation EBRT must still be validated and weighed against incremental increases in the risk of toxic effects (eg, rectal and bladder effects)”, they caution.

Editorialists Phillip Gray and Anthony Zietman, both from Massachusetts General Hospital in Boston, USA, concede that the dose–survival relationship seems to be “true”, but they urge readers to examine the suggestion of a causal link with “the eye of scrutiny”, especially in light of contrasting findings from randomised controlled trials.

They write: “Because information on disease-specific survival is not available in the [National Cancer Database], other factors may be contributing to the observed differences in overall survival.

“While Kalbasi et al made every attempt to adjust their models to account for this, such as including comorbidity scores, no statistical technique can fully account for unidentified confounding in a retrospective study.”